The First Total Synthesis of Solomonsterol B, a Marine Pregnane X Receptor Agonist

• Published in: European journal of organic chemistry Vol. 2012; no. 27; pp. 5187 - 5194
• Main Authors: Sepe, Valentina, Ummarino, Raffaella, D'Auria, Maria Valeria, Renga, Barbara, Fiorucci, Stefano, Zampella, Angela
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-09-2012; WILEY‐VCH Verlag; Wiley-VCH; Wiley Subscription Services, Inc
• Subjects: Alicyclic compounds, terpenoids, prostaglandins, steroids; Biological and medical sciences; Chemistry; Exact sciences and technology; General pharmacology; Medical sciences; Natural products; Organic chemistry; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Preparations and properties; Steroids; Structure-activity relationships; Total synthesis; Pregnane derivatives; Steroid; Agonist; Ligand; Pharmacognosy; Liver; Structure―activity relationships; Animal origin; Natural compound; Total synthesis; Characterization; Marine environment; Side chain; Gene; Structure activity relation; Porifera; Natural products; Isolation; Sponge; Invertebrata; Chemical synthesis; Steroids
• DOI: 10.1002/ejoc.201200619
• EISSN: 1099-0690
• ISSN: 1434-193X

A concise route to the pregnane X receptor (PXR) agonist solomonsterol B, a natural product isolated from the marine sponge Theonella swinhoei, has been developed starting from commercially available hyodeoxycholic acid. The synthesis features a one‐carbon side chain degradation and the refunctionalization of the A and B rings to install the desired trans junction and the two hydroxy groups at C2 and C3 in a trans relationship. The protocol proceeded with good yields (10 % over 13 steps), also allowing the preparation of a side chain‐modified derivative useful for a preliminary structure–activity relationship on PXR. The pharmacological characterization of solomonsterol B demonstrated that this compound was a PXR agonist in a transactivation assay, and when it was incubated with liver cells, it increased the expression of PXR‐regulated genes. These data support the development of sponge steroids as PXR ligands endowed with therapeutic potential.
We report the first total synthesis of solomonsterol B, a marine steroid endowed with potent agonistic activity towards the pregnane X receptor (PXR). This synthesis was completed in a total of 13 steps starting from hyodeoxycholic acid, with an overall yield of 10 %. The preparation of a side‐chain‐modified derivative and a preliminary structure–activity relationship on PXR is also reported.